+publisher:"University of Kansas" +contributor:("Reed, Gregory A.")

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University of Kansas

1. Zhang, Yuchen. IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2017, University of Kansas

URL: http://hdl.handle.net/1808/27333

► Many transporters are expressed at the basolateral membrane of human hepatocytes, including Organic Anion Transporting Polypeptide 1B1 (OATP1B1), OATP1B3, Organic Cation Transporter 1 (OCT1), Na+/Taurocholate… (more)

▼ Many transporters are expressed at the basolateral membrane of human hepatocytes, including Organic Anion Transporting Polypeptide 1B1 (OATP1B1), OATP1B3, Organic Cation Transporter 1 (OCT1), Na+/Taurocholate Cotransporting Polypeptide (NTCP) and more. These transporters are part of the absorption system of the liver, which is responsible for the uptake of chemicals from the portal vein into hepatocytes for further metabolism and elimination. Extensive studies have characterized the function of these transporters, and results suggest that liver uptake transporters, like OATP1B3 and OATP1B1, or OATP1B3 and NTCP, have many overlapping substrates. Because these transporters seem to play an essential role in the protection of the body from xenobiotics, it is important to better understand their function and how they interact with each other. In this dissertation, I focused on one of these transporter, OATP1B3, as a model transporter to improve the understanding of liver uptake transporters. OATP1B3 is responsible for the uptake of many endogenous compounds like bile acids and hormones as well as xenobiotics, including numerous drugs. Recent studies demonstrated that some of the liver uptake transporters like OATP1B1, OCT1 and NTCP can form homo-oligomers. In the first specific aim, I evaluated the hypothesis that OATP1B3 also can form homo-oligomers. To address this aim, co-immunoprecipitation and proximity ligation assays of differently tagged OATP1B3 were performed in transiently transfected HEK293 cells. The results demonstrated that OATP1B3 indeed can form homo-oligomers. In addition, uptake assays with wild-type and non-functional OATP1B3 suggested that the OATP1B3 unit in the homo-oligomers works as individual functional unit. Besides that, by using proximity ligation assays, the interaction between OATP1B3 and OATP1B1, and between OATP1B3 and NTCP was demonstrated in HEK293 cells. Interactions between OATP1B3 and NTCP were also confirmed in frozen liver sections. In the second specific aim, I evaluated the hypothesis that OATP1B3 can form hetero-oligomers with other transporters and that these interactions can influence their expression and function. I was able to extend the findings of hetero-oligomerization to include OCT1 using both immunoprecipitation and proximity ligation assays. Uptake assays and surface biotinylation experiments were performed with HEK293 cells co-expressing OATP1B3 and OCT1, OATP1B3 and OATP1B1, or OATP1B3 and NTCP. The results demonstrated that these interactions between OATP1B3 and the other transporters lead to changes in both, function and expression of OATP1B3 in a transporter-dependent manner. In the third specific aim, I evaluated the hypothesis that photoaffinity labeling can be used to study the binding sites and translocation pathways of OATP1B3. The known OATP1B3 substrate 8-fluorescein-cAMP (8-FcA) was used to perform photoaffinity labeling experiments with CHO Flp-In cells stably expressing His-tagged OATP1B3. The results suggested that 8-FcA can label proteins but background… Advisors/Committee Members: Hagenbuch, Bruno A (advisor), Blanco, V. Gustavo (cmtemember), Kasturi, Partha (cmtemember), Lampe, Jed N (cmtemember), Reed, Gregory A (cmtemember).

Subjects/Keywords: Pharmacology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Zhang, Y. (2017). IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/27333

Chicago Manual of Style (16^th Edition):

Zhang, Yuchen. “IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3.” 2017. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/27333.

MLA Handbook (7^th Edition):

Zhang, Yuchen. “IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3.” 2017. Web. 28 Jan 2021.

Vancouver:

Zhang Y. IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3. [Internet] [Doctoral dissertation]. University of Kansas; 2017. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/27333.

Council of Science Editors:

Zhang Y. IDENTIFICATION AND CHARACTERIZATION OF THE OLIGOMERIZATION AND STRUCTURAL FUNCTIONAL RELATIONSHIP OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 1B3. [Doctoral Dissertation]. University of Kansas; 2017. Available from: http://hdl.handle.net/1808/27333

University of Kansas

2. Ogilvie, Brian Wayne. AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2015, University of Kansas

URL: http://hdl.handle.net/1808/19459

► Clopidogrel is a thienopyridine antiplatelet prodrug that was approved by the US FDA in 1997 and quickly supplanted ticlopidine as the primary drug therapy for… (more)

▼ Clopidogrel is a thienopyridine antiplatelet prodrug that was approved by the US FDA in 1997 and quickly supplanted ticlopidine as the primary drug therapy for reducing atherothrombotic events. It is converted to its pharmacologically active metabolite H4, which irreversibly inactivates the P2Y12 receptor on platelets, through two sequential reactions that are catalyzed mainly by CYP2C19. Common clinical practice involved the coadministration of a proton pump inhibitor (PPI, including omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) with clopidogrel to decrease the risk of upper gastrointestinal bleeding. This practice was formalized for high risk patients by the American Heart Association (and others) in 2008. By 2009, numerous publications described an unexpected decrease in clopidogrel efficacy when coadministered with PPIs, prompting both the US Food & Drug Administration (FDA) and European Medicines Agency (EMA) to issue recommendations discouraging the concomitant use of PPIs and clopidogrel. Proton pump inhibitors are also metabolized by CYP2C19. It seemed reasonable to conclude that, despite their relatively short plasma half-lives, PPIs might competitively inhibit CYP2C19, thereby reducing the efficacy of clopidogrel. In 2010, as numerous publications emerged, both regulatory agencies restricted subsequent warnings to only omeprazole and esomeprazole. The interaction between clopidogrel and PPIs, and the potential mechanisms responsible for it, continues to be a subject of much debate in 2015. This dissertation describes research that contributes to the progress made in understanding the basis for the interaction between clopidogrel and PPIs since the time of the initial regulatory statements, and in particular, why only omeprazole and esomeprazole are implicated in this drug interaction. The initial studies in this dissertation identified omeprazole (a racemic mixture of R- and S-enantiomers) and esomeprazole (the S-enantiomer) as not only competitive inhibitors, but more importantly, metabolism-dependent inhibitors (MDIs) of CYP2C19 in human liver microsomes (HLM), human hepatocytes and recombinant CYP2C19. In contrast, lansoprazole and pantoprazole did not cause metabolism-dependent inhibition (MDI) of CYP2C19. In addition to its clinical relevance, these observations are important because they underscore the importance of using a low concentration of enzyme and a short incubation time with the CYP marker substrate in order to detect MDI of CYP enzymes in vitro. In many previous studies of CYP2C19 inhibition by omeprazole or esomeprazole, the concentration of HLM was too high and/or the substrate incubation time was too long to detect MDI. The kinetic parameters for CYP2C19 inactivation by omeprazole, namely kinact and KI, were determined and used in a physiologically based pharmacokinetic (PBPK) model to predict the degree of CYP2C19 inactivation under clinical conditions. Omeprazole and esomeprazole were subsequently shown to be irreversible MDIs of CYP2C19, which explained why the… Advisors/Committee Members: Reed, Gregory A (advisor), Parkinson, Andrew (advisor), Hagenbuch, Bruno (cmtemember), Weir, Scott (cmtemember), Hanzlik, Robert P (cmtemember).

Subjects/Keywords: Toxicology; Clopidogrel; Cytochrome P450; Drug-drug interactions; Esomeprazole; Omeprazole

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ogilvie, B. W. (2015). AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/19459

Chicago Manual of Style (16^th Edition):

Ogilvie, Brian Wayne. “AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL.” 2015. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/19459.

MLA Handbook (7^th Edition):

Ogilvie, Brian Wayne. “AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL.” 2015. Web. 28 Jan 2021.

Vancouver:

Ogilvie BW. AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL. [Internet] [Doctoral dissertation]. University of Kansas; 2015. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/19459.

Council of Science Editors:

Ogilvie BW. AN IN VITRO INVESTIGATION INTO THE MECHANISM OF THE CLINICALLY RELEVANT DRUG-DRUG INTERACTION BETWEEN OMEPRAZOLE OR ESOMEPRAZOLE AND CLOPIDOGREL. [Doctoral Dissertation]. University of Kansas; 2015. Available from: http://hdl.handle.net/1808/19459

3. Roth, Megan Elizabeth. Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3).

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2011, University of Kansas

URL: http://hdl.handle.net/1808/9715

► Organic anion transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Alterations in the function of the… (more)

▼ Organic anion transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Alterations in the function of the liver–specific OATP1B1 and OATP1B3 have been shown to affect the disposition of drugs throughout the body. It has been proposed that new drug candidates should be screened for possible OATP inhibition using a prototypical substrate such as estradiol–17β–glucuronide. However, there is evidence that OATPs may have multiple binding sites, and therefore screening with a single compound may be ineffective. Therefore, I tested the hypothesis that OATP1B3 has multiple overlapping but distinct binding sites, which are affected in substrate–dependent ways. This hypothesis was tested via two specific aims: 1) to identify and characterize substrate–dependent effects of plant compounds on OATP1B3–mediated transport, and 2) to identify regions of OATP1B3 involved in the binding and/or translocation of individual model substrates. In the first specific aim, interacting compounds were identified by screening a library of plant compounds for inhibition or stimulation of OATP–mediated uptake of two model substrates. Completion of this specific aim identified two structurally similar compounds that produce substrate–dependent effects on OATP1B3–mediated transport. These compounds stimulate transport of estrone–3–sulfate by increasing substrate affinity. However, the compounds either inhibit or have no effect on the uptake of estradiol–17β–glucuronide. These results demonstrate that estrone–3–sulfate and estradiol–17β–glucuronide have distinct binding sites on OATP1B3. In specific aim two, thirty–three amino acids in the first transmembrane domain and extracellular loop of OATP1B3 were individually mutated to cysteines, and I determined the effect of these mutations on the transport of estradiol-17β-glucuronide and estrone–3–sulfate. Five of the cysteine–substituted OATP1B3 mutants produced different effects on transporter function depending upon the substrate tested. These results suggest that this region of OATP1B3 is involved in the recognition and translocation of individual model substrates. This dissertation demonstrates that OATP1B3 has distinct binding sites for estradiol–17β–glucuronide and estrone–3–sulfate. Furthermore, it shows that transport of these two model substrates is affected in different ways by the same compounds. This knowledge can be used to improve screening of drug candidates to prevent adverse drug–drug interactions prior to the occurrence of adverse events. Advisors/Committee Members: Hagenbuch, Bruno (advisor), Krishnamurthy, Partha (cmtemember), Reed, Gregory A. (cmtemember), Timmermann, Barbara N (cmtemember), Zhu, Bao-Ting (cmtemember).

Subjects/Keywords: Pharmacology; Physiology; Drug-drug interactions; Oatp; Structure-function; Transporters

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Roth, M. E. (2011). Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3). (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/9715

Chicago Manual of Style (16^th Edition):

Roth, Megan Elizabeth. “Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3).” 2011. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/9715.

MLA Handbook (7^th Edition):

Roth, Megan Elizabeth. “Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3).” 2011. Web. 28 Jan 2021.

Vancouver:

Roth ME. Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3). [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/9715.

Council of Science Editors:

Roth ME. Substrate Dependent Alterations of Organic Anion Transporting Polypeptide 1B3 (OATP1B3). [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/9715

University of Kansas

4. Flynn, Colleen A. FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2011, University of Kansas

URL: http://hdl.handle.net/1808/9723

► Transporters play a major role in the absorption and disposition of fexofenadine, suggesting this drug could be used as a probe of transporter activity. When… (more)

▼ Transporters play a major role in the absorption and disposition of fexofenadine, suggesting this drug could be used as a probe of transporter activity. When fexofenadine was administered in combination with four drugs (buspirone, caffeine, dextromethorphan and losartan) used to probe cytochrome P450 (CYP) activities, a significant decrease in fexofenadine AUC was observed without a change in elimination. Based on this observation, I hypothesized a fexofenadine-probe drug interaction was occurring during oral absorption, and that this interaction was occurring at an enterocyte-expressed OATP. This interaction was reproduced and studied using in vitro model systems. In Specific Aim 1, a specific LC-MS/MS method was developed and validated for the quantification of fexofenadine and the other four probe drugs for use in the remaining specific aims. In Specific Aim 2, the interaction between fexofenadine and four enterocyte- and hepatocyte-expressed OATPs was characterized, and OATP1A2 was identified as the most effective transporter of fexofenadine, with a Km of 35 μM. Because fexofenadine was efficiently transported by OATP1A2, the four CYP probe drugs were tested as inhibitors of OATP1A2-mediated fexofenadine transport in Specific Aim 3. Buspirone, losartan, and dextromethorphan each inhibited OATP1A2-mediated fexofenadine transport in a concentration dependent manner. This inhibition could explain the decrease in fexofenadine oral bioavailability seen in the clinical study we had previously conducted. The replication of the fexofenadine-probe drug interaction in this model system supports the conclusion that OATP1A2 is the major uptake transporter for fexofenadine absorption in the enterocyte, and suggests that fexofenadine may be an effective probe drug for this transporter. In Specific Aim 4, I further characterized the fexofenadine-probe drug interactions using the three known OATP1A2 polymorphisms: Ile13Thr, Arg168Cys, and Glu172Asp. While the mutants functioned as expected with regard to fexofenadine transport, the presence of the mutation did not alter the observed drug-drug interactions seen previously with OATP1A2 and the CYP probes. Taking these data into account, it appears the fexofenadine-drug interaction seen previously is not affected by single nucleotide polymorphisms. This work demonstrates that OATP1A2 is capable of transporting fexofenadine and that several CYP probe drugs inhibit its transport by OATP1A2. This latter observation limits the utility of fexofenadine to be used as a single probe, rather than as part of a probe drug cocktail. Advisors/Committee Members: Reed, Gregory A (advisor), Durham, Dianne (cmtemember), Hagenbuch, Bruno (cmtemember), Lampe, Jed N. (cmtemember), Pazdernik, Thomas L. (cmtemember).

Subjects/Keywords: Toxicology; Drug-drug interactions; Fexofenadine; Oatp; Probe cocktail; Single nucleotide polymorphism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Flynn, C. A. (2011). FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/9723

Chicago Manual of Style (16^th Edition):

Flynn, Colleen A. “FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS.” 2011. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/9723.

MLA Handbook (7^th Edition):

Flynn, Colleen A. “FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS.” 2011. Web. 28 Jan 2021.

Vancouver:

Flynn CA. FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS. [Internet] [Doctoral dissertation]. University of Kansas; 2011. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/9723.

Council of Science Editors:

Flynn CA. FEXOFENADINE AND ORGANIC ANION TRANSPORTING POLYPEPTIDES (OATPs): TRANSPORT AND DRUG-DRUG INTERACTIONS. [Doctoral Dissertation]. University of Kansas; 2011. Available from: http://hdl.handle.net/1808/9723

University of Kansas

5. Boxberger, Kelli Harmon. IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2018, University of Kansas

URL: http://hdl.handle.net/1808/27078

► The human organic cation transporter 1 (hOCT1) is a polyspecific transporter, primarily expressed in the liver, which is known to interact with a large number… (more)

▼ The human organic cation transporter 1 (hOCT1) is a polyspecific transporter, primarily expressed in the liver, which is known to interact with a large number of structurally dissimilar compounds. Several clinically-relevant drugs, as well as some endogenous compounds and other xenobiotics have been shown to be transported by or inhibit hOCT1. Due to its hepatic expression and general ADME function, hOCT1 has been implicated in adverse drug events (ADEs), including drug-drug interactions. As such, multiple regulatory agencies recommend including hOCT1, in pre-clinical transporter interaction studies. Limited structural information is available for hOCT1, and recently, endogenous functions and substrate-dependent effects have been identified for close relatives of hOCT1. Taken together, these suggest a need for further scrutiny of hOCT1 structure-activity relationships for development of critical drug-transporter interaction studies. The hypothesis was developed that both endogenous and xenobiotic compounds modulate the functional activity of hOCT1 in a substrate-dependent manner through interaction with specific, but perhaps distinct ligand-binding domains within the transporter. The hypothesis was tested via the following specific aims: 1) investigate the effect of xenobiotics on endogenous substrate transport by hOCT1, 2) identify and characterize substrate-dependent interactions with hOCT1, and 3) examine the role of the extracellular loop domain of hOCT1 in substrate affinity and translocation. In the first specific aim, dopamine and serotonin were identified as substrates for hOCT1. Serotonin proved to be a moderate-affinity substrate, while hOCT1 was able to transport it at high capacity. Several clinically-relevant drugs inhibited hOCT1-mediated serotonin transport, and these results were capitulated in primary human hepatocytes. Combined data from this inhibition screen and those previously published by other groups suggested the possibility of substrate-dependent effects. In specific aim two, substrate-dependent effects were screened for in a relatively new assay method, competitive counterflow (CCF). The CCF assay allowed for identification of novel substrates for hOCT1, including negatively-charged bromosulfophthalein (BSP). CCF results also identified numerous substrate-dependent effects which were explored further using computational (homology) modeling and ligand docking. Docking experiments identified three distinct binding sites within the hOCT1 homology model which explain several of the overserved substrate-dependent interactions, and supports previous claims that hOCT1 has a large substrate binding region versus a singular binding site and may be the reason for hOCT1’s polyspecificity. In the final specific aim, an attempt was made to generate human and rat OCT1 chimeric proteins. The goal of this study was to examine the role of the extracellular loop (ECL) domain in the observed differences in substrate affinity between species. Issues during the cloning process prevented the completion of this… Advisors/Committee Members: Hagenbuch, Bruno (advisor), Lampe, Jed N (cmtemember), Pritchard, Michele T (cmtemember), Reed, Gregory A (cmtemember), Blanco, V. Gustavo (cmtemember).

Subjects/Keywords: Pharmacology; computational modeling; drug disposition; drug-drug interactions; organic cation transporter; substrate-dependent interactions; transporters

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Boxberger, K. H. (2018). IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/27078

Chicago Manual of Style (16^th Edition):

Boxberger, Kelli Harmon. “IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1.” 2018. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/27078.

MLA Handbook (7^th Edition):

Boxberger, Kelli Harmon. “IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1.” 2018. Web. 28 Jan 2021.

Vancouver:

Boxberger KH. IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1. [Internet] [Doctoral dissertation]. University of Kansas; 2018. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/27078.

Council of Science Editors:

Boxberger KH. IDENTIFICATION OF ENDOGENOUS FUNCTION AND SUBSTRATE-DEPENDENT INTERACTIONS OF ORGANIC CATION TRANSPORTER 1. [Doctoral Dissertation]. University of Kansas; 2018. Available from: http://hdl.handle.net/1808/27078

6. Williams, Clarence David. Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2012, University of Kansas

URL: http://hdl.handle.net/1808/10290

► Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. APAP is metabolized to a reactive metabolite that causes hepatotoxicity in… (more)

▼ Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. APAP is metabolized to a reactive metabolite that causes hepatotoxicity in a dose-dependent manner. A series of cascading intracellular events lead to cellular necrosis; this necrosis initiates a sterile inflammatory response which includes the production of multiple cytokines and chemokines that in turn recruit innate immune cells into the liver. Many of the inflammatory or corresponding anti-inflammatory mediators that are produced in this process have been linked to alterations in the subsequent injury as well as the injury resolution. This dissertation focuses on one particular inflammatory mediator, interleukin-1â (IL-1â), and its ability to modulate neutrophil priming, activation and hepatic recruitment. We show that mature IL-1â is produced during APAP overdose in a caspase dependent manner (Nalp3 inflammasome) which can be inhibited in vivo by a pan-caspase inhibitor, and that IL-1â is capable of activating neutrophils in vivo. However, the limited amount of IL-1â produced during APAP overdose is insufficient to activate or recruit neutrophils into the liver. In confirmation of these findings, genetic elimination of the components of the Nalp3 inflammasome or the IL-1 receptor does not alter APAP-induced injury or neutrophil recruitment. It has previously been shown that neutrophils do not participate in APAP-induced injury. This has been demonstrated in various ways, however, controversy arose when pretreatment of mice with neutropenia-inducing antibody resulted in protection from APAP toxicity. To further clarify this matter, CD18-deficient mice were subjected to APAP overdose, and in agreement with previous findings these mice were not protected from APAP overdose. Next we functionally characterized neutrophils during APAP overdose to further confirm that neutrophils do not participate in exacerbation of injury. Interestingly, during injury resolution neutrophils become activated especially in peripheral blood but did not have enhanced reactive oxygen priming in the liver. These findings were confirmed with NADPH oxidase deficient mice which had no alteration in injury resolution. Interestingly, these data were very similar to neutrophil function in human APAP overdose patients. These data indicate that activation of neutrophils might be critical for maintaining host defense during hepatic impairment. As a whole, this dissertation shows IL-1â is a minor participant in the sterile inflammatory response following APAP overdose, but this response is critical for neutrophil activation and eventual injury resolution. Advisors/Committee Members: Jaeschke, Hartmut (advisor), Apte, Udayan (cmtemember), Levant, Beth (cmtemember), Reed, Gregory A. (cmtemember), Weinman, Steve A. (cmtemember).

Subjects/Keywords: Toxicology; Acetaminophen; Il-1beta; Neutrophil

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Williams, C. D. (2012). Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/10290

Chicago Manual of Style (16^th Edition):

Williams, Clarence David. “Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose.” 2012. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/10290.

MLA Handbook (7^th Edition):

Williams, Clarence David. “Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose.” 2012. Web. 28 Jan 2021.

Vancouver:

Williams CD. Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose. [Internet] [Doctoral dissertation]. University of Kansas; 2012. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/10290.

Council of Science Editors:

Williams CD. Role of Interleukin-1beta and neutrophil activation during acetaminophen overdose. [Doctoral Dissertation]. University of Kansas; 2012. Available from: http://hdl.handle.net/1808/10290

7. Hays, Amanda Lynne. Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2012, University of Kansas

URL: http://hdl.handle.net/1808/11446

► Organic Anion Transporting Polypeptides (OATPs) are multispecific transport proteins that mediate the uptake of numerous endogenous and exogenous compounds into cells. Recently, OATPs have been… (more)

▼ Organic Anion Transporting Polypeptides (OATPs) are multispecific transport proteins that mediate the uptake of numerous endogenous and exogenous compounds into cells. Recently, OATPs have been shown to have altered expression in cancer tissue compared to their normal expression profiles. It has been proposed that OATPs can be targeted to improve cancer therapeutics. Therefore, I tested the hypothesis that expression of OATPs in cancer combined with their ability to transport cytotoxic anticancer drugs makes them potential targets for improving cancer diagnosis and therapy. The hypothesis was tested via the following specific aims: 1) to identify and characterize OATP expression in cancer, 2) to identify novel anticancer drug substrates of OATPs, and 3) to identify novel cytotoxic compounds from plant extracts that are substrates of OATPs and can be developed into anticancer drugs that target OATP-expressing cancers. In the first specific aim, OATPs expressed in pancreatic cancer were identified by immunohistochemical staining of pancreatic cancer tissue specimens. Completion of this specific aim identified four major OATPs expressed in pancreatic adenocarcinomas. Additionally, OATP1B3 expression was observed to be highest in low stage adenocarcinoma and absent in metastatic tissue. These results demonstrate that OATP1B3 may serve as a diagnostic marker and/or therapeutic target in early stage adenocarcinomas. In specific aim two, novel anticancer drug substrates of OATP1B3 were identified by screening the NCI/DTP oncology drug set containing all of the FDA approved chemotherapy drugs. In this study, I determined the effect of the anticancer drugs on transport and cell viability of OATP1B3-expressing cells. Finally, I demonstrated that the anticancer drugs etoposide, oxaliplatin and plicamycin are substrates of OATP1B3. These results suggest that the mentioned cytotoxic anticancer drugs could potentially be used to treat OATP1B3-expressing cancers. In the last specific aim, Kansas plant extracts were screened using bioassay guided fractionation and cell viability assays to isolate novel cytotoxic compounds that are substrates of OATP1B3. Given that these novel plant compounds are cytotoxic and are also transported by OATP1B3 suggests that they can be used for lead optimization studies to develop new anticancer drug entities. This dissertation demonstrates that OATP1B3 is a potential target for mechanisms of OATP-mediated anticancer therapy. Ultimately, this knowledge can be used to utilize OATP1B3 expression in cancer as a diagnostic marker, as well as a target for cytotoxic anticancer drug therapies. Advisors/Committee Members: Hagenbuch, Bruno (advisor), Apte, Udayan (cmtemember), Geiger, Paige C (cmtemember), Reed, Gregory A. (cmtemember), Zhu, Bao-Ting (cmtemember).

Subjects/Keywords: Pharmacology; Cancer; Oatp; Transporters

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APA (6^th Edition):

Hays, A. L. (2012). Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/11446

Chicago Manual of Style (16^th Edition):

Hays, Amanda Lynne. “Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy.” 2012. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/11446.

MLA Handbook (7^th Edition):

Hays, Amanda Lynne. “Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy.” 2012. Web. 28 Jan 2021.

Vancouver:

Hays AL. Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy. [Internet] [Doctoral dissertation]. University of Kansas; 2012. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/11446.

Council of Science Editors:

Hays AL. Targeting Organic Anion Transporting Polypeptides in Cancer to Improve Diagnostics and Therapy. [Doctoral Dissertation]. University of Kansas; 2012. Available from: http://hdl.handle.net/1808/11446

8. McGill, Mitchell Ryan. Acetaminophen Hepatotoxicity in Humans and Mice.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2013, University of Kansas

URL: http://hdl.handle.net/1808/12178

► Acetaminophen (APAP) is a popular analgesic and antipyretic. Most of a therapeutic dose is glucuronidated or sulfated and excreted. A small amount is converted by… (more)

▼ Acetaminophen (APAP) is a popular analgesic and antipyretic. Most of a therapeutic dose is glucuronidated or sulfated and excreted. A small amount is converted by cytochromes P450 to the reactive electrophile N-acetyl-p-benzoquinone imine (NAPQI). Fortunately, NAPQI can be detoxified by conjugation with glutathione (GSH). However, after an overdose the glucuronidation and sulfation pathways are overwhelmed, resulting in formation of excess NAPQI which depletes GSH and binds proteins. This causes mitochondrial dysfunction and oxidative stress. Oxidative stress activates the c-Jun N-terminal kinase, which translocates to mitochondria and exacerbates the injury. The result is hepatocyte death. Though well-established in mice, less work has been done with human models. Our goal was to further investigate the role of mitochondria in mice and to begin studying the mechanisms of hepatotoxicity in humans. A comparison of rats and mice supported the role of mitochondria in mice. Using the human liver cell line HepaRG, we found that protein binding, loss of mitochondrial potential, and oxidative stress preceded injury. Finally, using novel mechanistic plasma biomarkers, we have provided evidence that mitochondrial damage may also occur in APAP overdose patients, leading to oncotic necrosis. Recently, it was proposed that serum APAP-protein adducts can be used to diagnose APAP overdose. However, little work has been done to characterize the dose-response and timecourse of this parameter. We found that liver GSH depletion isn't required for protein binding in mice and that binding occurred without toxicity. Importantly, APAP-protein adducts could be measured in plasma without liver injury. The mechanism by which this occurs likely involves secretion of proteins adducted within hepatocytes, though other mechanisms couldn't be ruled out. Finally, liver injury caused by ischemia-reperfusion increased APAP-protein adducts in mouse plasma after a subtoxic dose. Our data support the use of APAP-protein adducts in plasma, but urge consideration of potential confounding factors. Advisors/Committee Members: Jaeschke, Hartmut (advisor), Ding, Wen-Xing (cmtemember), Lampe, Jed N. (cmtemember), Reed, Gregory A. (cmtemember), Weinman, Steven A. (cmtemember).

Subjects/Keywords: Toxicology; Physiology; Pathology; Acetaminophen; Human; Liver; Mitochondria; Translational research

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APA (6^th Edition):

McGill, M. R. (2013). Acetaminophen Hepatotoxicity in Humans and Mice. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/12178

Chicago Manual of Style (16^th Edition):

McGill, Mitchell Ryan. “Acetaminophen Hepatotoxicity in Humans and Mice.” 2013. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/12178.

MLA Handbook (7^th Edition):

McGill, Mitchell Ryan. “Acetaminophen Hepatotoxicity in Humans and Mice.” 2013. Web. 28 Jan 2021.

Vancouver:

McGill MR. Acetaminophen Hepatotoxicity in Humans and Mice. [Internet] [Doctoral dissertation]. University of Kansas; 2013. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/12178.

Council of Science Editors:

McGill MR. Acetaminophen Hepatotoxicity in Humans and Mice. [Doctoral Dissertation]. University of Kansas; 2013. Available from: http://hdl.handle.net/1808/12178

9. Healy-Stoffel, Michelle Renee. EFFECTS OF A UNILATERAL INTRASTRIATAL 6-HYDROXYDOPAMINE MODEL OF EARLY PARKINSON'S DISEASE ON MIDBRAIN DOPAMINE NEURONS IN RATS: A STEREOLOGICAL STUDY.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2013, University of Kansas

URL: http://hdl.handle.net/1808/12268

► Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic function, leading to the classical clinical signs of tremor, bradykinesia and loss… (more)

▼ Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by loss of dopaminergic function, leading to the classical clinical signs of tremor, bradykinesia and loss of postural balance. These motor symptoms occur late in the disease, and since the treatments for late-stage PD are largely ineffective, a better understanding of the early stages of PD is needed in order to prevent and treat the disease. The early disease process is still poorly understood, however, and current difficulties in diagnosing prodromal or very early-stage PD make clinical studies challenging. Therefore, animal models of early PD are an invaluable resource in discovering the neuropathological, behavioral and biochemical features of the early stages of neurodegeneration found in PD. Early PD is associated with non-motor clinical signs such as changes to sleep patterns, olfactory functions, cognition and mood; while gross motor function is largely compensated for until the later stages of dopaminergic neurodegeneration. The nature of these early clinical signs presents a challenge when assessing PD models, however, as subtle sensory and affective changes can be difficult to quantify in animals. The goal of this work, therefore, was to investigate morphological changes to the dopamine neurons most implicated in the development of PD. Morphological endpoints, which can be robustly quantified using unbiased stereological analysis, provide information about the changes occurring to the neuronal structure during the neurodegenerative process, and offer promise as an objective method to assess the conditions which render dopamine neurons vulnerable in PD, as well as to evaluate new neuroprotectants and therapeutic interventions in early PD animal models. A deficiency in n-3 polyunsaturated fatty acids (n-3 PUFAs), which have been shown to be neuroprotective, has been proposed as a potential factor in the vulnerability of dopamine neurons to PD. In order to determine the effects of n-3 PUFA deficiency on substantia nigra pars compacta (SNpc) dopamine neurons, morphological, behavioral and biochemical endpoints were investigated in the unilateral intrastriatal 6-hydroxydopamine (6-OHDA) model of early to moderate Parkinson's disease in Aim 1. In addition, a method was developed to use a novel staining method combining tyrosine hydroxylase (TH) staining with silver nucleolar (AgNOR) staining and stereological analysis techniques to quantify the morphological changes induced by 6-OHDA lesion in dopaminergic neurons in Aim 2. In Aim 3, this method was then expanded to investigate morphological changes to the dopaminergic nucleoli stained with AgNOR, which may lend valuable insights into the role of the nucleolus in early PD. In Aim 4 the cumulative techniques developed in the previous aims were employed to determine the differential morphological changes to the dopamine neurons and their nucleoli in the A8, A9 and A10 subpopulations of midbrain dopamine neurons, which correspond to the retrorubral field (RRF), SNpc, and ventral… Advisors/Committee Members: Levant, Beth (advisor), Ahmad, Syed O (cmtemember), Stanford, John A (cmtemember), Pazdernik, Thomas L. (cmtemember), Weir, Scott J (cmtemember), Reed, Gregory A. (cmtemember).

Subjects/Keywords: Neurosciences; Neurogeneration; Nucleolus; Parkinson's disease; Staining; Stereology; Substantia nigra

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APA (6^th Edition):

Healy-Stoffel, M. R. (2013). EFFECTS OF A UNILATERAL INTRASTRIATAL 6-HYDROXYDOPAMINE MODEL OF EARLY PARKINSON'S DISEASE ON MIDBRAIN DOPAMINE NEURONS IN RATS: A STEREOLOGICAL STUDY. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/12268

Chicago Manual of Style (16^th Edition):

Healy-Stoffel, Michelle Renee. “EFFECTS OF A UNILATERAL INTRASTRIATAL 6-HYDROXYDOPAMINE MODEL OF EARLY PARKINSON'S DISEASE ON MIDBRAIN DOPAMINE NEURONS IN RATS: A STEREOLOGICAL STUDY.” 2013. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/12268.

MLA Handbook (7^th Edition):

Vancouver:

Healy-Stoffel MR. EFFECTS OF A UNILATERAL INTRASTRIATAL 6-HYDROXYDOPAMINE MODEL OF EARLY PARKINSON'S DISEASE ON MIDBRAIN DOPAMINE NEURONS IN RATS: A STEREOLOGICAL STUDY. [Internet] [Doctoral dissertation]. University of Kansas; 2013. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/12268.

Council of Science Editors:

Healy-Stoffel MR. EFFECTS OF A UNILATERAL INTRASTRIATAL 6-HYDROXYDOPAMINE MODEL OF EARLY PARKINSON'S DISEASE ON MIDBRAIN DOPAMINE NEURONS IN RATS: A STEREOLOGICAL STUDY. [Doctoral Dissertation]. University of Kansas; 2013. Available from: http://hdl.handle.net/1808/12268

University of Kansas

10. Pacyniak, Erik Kristofer. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7717

► Polybrominated diphenyl ethers (PBDEs) were introduced in the late 1970's as additive flame retardants incorporated into textiles, electronics, plastics and furniture. Although 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209)… (more)

▼ Polybrominated diphenyl ethers (PBDEs) were introduced in the late 1970's as additive flame retardants incorporated into textiles, electronics, plastics and furniture. Although 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE209) is the only congener currently on the market, 2,2`,4,4`-tetrabromodiphenyl ether (BDE47), 2,2`,4,4`,5-pentabromodiphenyl ether (BDE99), and 2,2`,4,4`,5,5`-hexabromodiphenyl ether (BDE153) are the predominant congeners detected in human and wildlife samples. Upon exposure, PBDEs enter the liver where they are biotransformed to potentially toxic metabolites. Although the human liver burden of PBDEs is not clear, the presence of PBDEs in human liver is particularly alarming because it has been demonstrated in rodents that hydroxylated metabolites may play a pivotal role in PBDE-mediated toxicity. The mechanism by which PBDEs enter the liver was not known. However, due to their large molecular weights (MWs ~485 to 1000 Da), they were not likely to enter hepatocytes by simple diffusion. Organic anion transporting polypeptides (OATPs: human; Oatps: rodents) are responsible for hepatic uptake of a variety of amphipathic compounds of MWs larger than 350 Da. Therefore, I tested the hypothesis that OATPs/Oatps expressed in human and mouse hepatocytes are responsible for the uptake of PBDE congeners 47, 99, and 153 by using Chinese hamster ovary (CHO) cell lines expressing OATP1B1, OATP1B3, or OATP2B1 and Human Embryonic Kidney 293 (HEK293) cells transiently expressing Oatp1a1, Oatp1a4, Oatp1b2, or Oatp2b1. Direct uptake studies illustrated that PBDE congeners are substrates of human and mouse hepatic OATPs/Oatps, except for Oatp1a1. Detailed kinetic analysis revealed that OATP1B1, OATP1B3, Oatp1a4, and Oatp1b2 transport BDE47 with the highest affinity followed by BDE99 and BDE153. However, both OATP2B1 and Oatp2b1 transported all three congeners with similar affinities. The importance of hepatic Oatps for the accumulation of BDE47 in liver was confirmed using Oatp1a4- and Oatp1b2-null mice. These results clearly suggest that uptake of PBDEs via these OATPs/Oatps are responsible for liver-specific accumulation of PBDEs. In mouse liver, PBDEs induce drug metabolizing enzymes, namely cytochrome P450s (Cyps). However, the molecular mechanisms underlying this induction was unknown. Cyp2b10 and 3a11 are target genes of the xenobiotic nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both of which are responsible for mediating induction of Cyp2b10 and Cyp3a11, respectively. I hypothesized that PBDE congeners are CAR and/or PXR activators. Using reporter-gene luciferase assays I showed that BDE47, BDE99 and BDE209 activate human and mouse CAR and PXR in a concentration-dependent manner. Furthermore, induction of Cyp2b10 and Cyp3a11 was markedly suppressed in CAR- and PXR-null mice, respectively, indicating that PBDE congeners activate these receptors in vivo. BDE47 and BDE99, the primary congeners detected in humans in the United States, are capable of inducing… Advisors/Committee Members: Guo, Grace L. (advisor), Hagenbuch, Bruno (cmtemember), Klaassen, Curtis D. (cmtemember), Reed, Gregory A. (cmtemember), Petroff, Brian K. (cmtemember).

Subjects/Keywords: Toxicology; Constitutive androstane receptor; Nuclear receptors; Organic anion transporting polypeptide; Polybrominated diphenyl ethers; Pregnane x receptor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pacyniak, E. K. (2010). Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7717

Chicago Manual of Style (16^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/7717.

MLA Handbook (7^th Edition):

Pacyniak, Erik Kristofer. “Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver.” 2010. Web. 28 Jan 2021.

Vancouver:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/7717.

Council of Science Editors:

Pacyniak EK. Molecular Mechanism of Polybrominated Diphenyl Ether Disposition in the Liver. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7717

University of Kansas

11. Reisman, Scott Aaron. PHARMACOLOGIC AND TRANSGENIC ACTIVATION OF NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) ALTERS KINETICS AND TOXICODYNAMICS OF XENOBIOTICS.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2008, University of Kansas

URL: http://hdl.handle.net/1808/4325

► Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, which, upon translocation into the nucleus, is capable of inducing a variety of cytoprotective… (more)

▼ Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, which, upon translocation into the nucleus, is capable of inducing a variety of cytoprotective genes, such as NAD(P)H:quinone oxidoreductase 1 (Nqo1), glutamate-cysteine ligase, catalytic subunit (Gclc), glutathione-S-transferases (Gsts), and multidrug-associated resistance proteins (Mrps). Because Nrf2 can induce many cytoprotective enzymes and transporters, it is a potential target for the prevention of liver injury, for which there are limited treatments. Therefore, it was hypothesized that pharmacologic activation of Nrf2 would protect against acetaminophen (AA) hepatotoxicity, and that genetic ablation and enhancement of Nrf2 activation would alter pharmacokinetics of AA and sulfobromopthalein (BSP). Pharmacokinetic analysis will provide insight into a potentially novel hepatoprotective role for Nrf2. It was determined whether the natural triterpenoid oleanolic acid and a synthetic derivative 2-cyano-3,12-dioxooleana-1,9-diene-28-imidazolide (CDDO-Im) could protect liver from AA toxicity through activation of Nrf2. Oleanolic acid increased mRNA expression of the Nrf2 target genes Nqo1, Gclc, and heme oxygenase-1 (Ho-1) in wild-type but not in Nrf2-null mice, and protected against acetaminophen hepatotoxicity in wild-type mice, but to a lesser extent in Nrf2-null mice. The synthetic triterpenoid CDDO-Im also protected the liver from AA-induced injury and induced the Nrf2 target genes Nqo1, Gclc, and Ho-1 in a dose- and time-dependent manner. In contrast, this protection and mRNA induction was ablated in Nrf2-null mice. These studies demonstrate that oleanolic acid and CDDO-Im protect the liver from AA-induced injury by activating the antioxidant transcription factor Nrf2. A recently engineered mouse with knockdown of Keap1 (Keap1-kd mice), the cytosolic repressor of Nrf2, has a 55% decrease in Keap1 mRNA and a 200% increase in Nrf2 protein in liver. Several experiments with Nrf2-null mice have demonstrated the effects of a lack of Nrf2. However, little is known about the biological effects of more Nrf2 activation. Accordingly, the phenotype of Keap1-kd mice, as well as mRNA expression of detoxifying and antioxidant genes, were compared with Nrf2-null and wild-type mice. The present study revealed three patterns of gene expression, which collectively suggest that hepatic Nrf2 is more important for the detoxification and elimination of electrophiles rather than reactive oxygen species. Numerous studies have shown that Nrf2 protects against toxicity, which is frequently attributed to decreased toxicodynamic effects of chemical insults, as exemplified by increased expression of cytoprotective genes. However, the effects of Nrf2 on the kinetics of xenobiotics have not been examined. It was found that Nrf2 increases biliary excretion of BSP by increasing glutathione (GSH) conjugation and biliary excretion of the BSP conjugate. In addition, lack of Nrf2 decreases AA glucuronidation, leading to increased NAPQI formation and hepatotoxicity,… Advisors/Committee Members: Klaassen, Curtis D. (advisor), Copple, Bryan (cmtemember), Guo, Grace (cmtemember), Reed, Gregory A. (cmtemember), Andrews, Glen K. (cmtemember).

Subjects/Keywords: Health sciences; Toxicology; Pharmacology; Acetaminophen; Electrophilic stress; Glutathione-s-transferases; Nad(p)h:quinone oxidoreductase; Nrf2; Oxidative stress

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Reisman, S. A. (2008). PHARMACOLOGIC AND TRANSGENIC ACTIVATION OF NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) ALTERS KINETICS AND TOXICODYNAMICS OF XENOBIOTICS. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/4325

Chicago Manual of Style (16^th Edition):

Reisman, Scott Aaron. “PHARMACOLOGIC AND TRANSGENIC ACTIVATION OF NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) ALTERS KINETICS AND TOXICODYNAMICS OF XENOBIOTICS.” 2008. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/4325.

MLA Handbook (7^th Edition):

Reisman, Scott Aaron. “PHARMACOLOGIC AND TRANSGENIC ACTIVATION OF NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) ALTERS KINETICS AND TOXICODYNAMICS OF XENOBIOTICS.” 2008. Web. 28 Jan 2021.

Vancouver:

Reisman SA. PHARMACOLOGIC AND TRANSGENIC ACTIVATION OF NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) ALTERS KINETICS AND TOXICODYNAMICS OF XENOBIOTICS. [Internet] [Doctoral dissertation]. University of Kansas; 2008. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/4325.

Council of Science Editors:

Reisman SA. PHARMACOLOGIC AND TRANSGENIC ACTIVATION OF NUCLEAR FACTOR-ERYTHROID 2-RELATED FACTOR 2 (NRF2) ALTERS KINETICS AND TOXICODYNAMICS OF XENOBIOTICS. [Doctoral Dissertation]. University of Kansas; 2008. Available from: http://hdl.handle.net/1808/4325

University of Kansas

12. Weaver, Yi Miao. STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2010, University of Kansas

URL: http://hdl.handle.net/1808/7394

► The organic anion transporting polypeptides (human: OATP; other: Oatp) form a mammalian transporter superfamily that mediates the transport of structurally unrelated compounds across the cell… (more)

▼ The organic anion transporting polypeptides (human: OATP; other: Oatp) form a mammalian transporter superfamily that mediates the transport of structurally unrelated compounds across the cell membrane. Members in this superfamily participate in the absorption, distribution and excretion of many endogenous and exogenous substances including a number of medications and environmental toxicants. Polymorphisms of OATPs have been shown clinically to give rise to inter-individual variabilities of drug efficacy and/or toxicity. Furthermore, as multi-specific transporters, they are potential sites for drug-drug interactions. Therefore, understanding the mechanism of OATP/Oatp mediated transport of endo- and xenobiotics will not only help to improve drug efficacy but also to improve the prediction and prevention of toxicity. The overall goal of this dissertation is identifying key amino acids that may play an important role in OATP/Oatp-mediated transport and investigating the spatial size of the substrate binding/translocation pocket. In this dissertation, I defended three specific aims. In the first specific aim, I evaluated the hypothesis that conserved positively charged amino acids play important roles in OATP1B1 transport function. To address this aim, site-directed mutagenesis was employed and the mutants of several conserved positively charged amino acids were studied. The two extracellular amino acids R57 and K361 were found to be important in OATP1B1 mediated transport of estradiol-17β-glucuronide, estrone-3-sulfate and BSP. In the second specific aim, I evaluated the hypothesis that quantifying transport activities of different substrates mediated by chimeras between rat Oatp1a1 and Oatp1a4 in combination with site-directed mutagenesis should allow us to identify regions and/or individual amino acids that are important for Oatp1a4-mediated substrate recognition and/or transport. The effects of chimeric proteins on transport activity were substrate dependent. Extracellular loop 4 and transmembrane domain 8 were identified to be important in transport of digoxin, taurocholate and estradiol-17β-glucuronide. The C-terminal half of Oatp1a4 and Oatp1a1 was found to be important for BSP transport and the interactions between the N-terminal half and the C-terminal half of Oatp1a4 is essential for DPDPE transport. In the third specific aim, I evaluated the hypothesis that different rat renal organic anion transporters of the Oat and Oatp families selectively transport perfluorinated carboxylates (PFCAs) depending on the chain lengths. The purpose of this study was to determine the substrate size selectivity of Oats and Oatp1a1. To address this aim, the inhibitory effects of PFCAs with chain length from C2 to C18 on transport of model substrates by rat Oat1, Oat2, Oat3, Urat1 and Oatp1a1 was quantified. Furthermore, direct uptake of the best inhibitors was characterized. The best substrates for Oats were C7 and C8, whereas Oatp1a1 transported longer PFCAs such as C9 and C10 better than C8 and C7. Altogether, this dissertation… Advisors/Committee Members: Hagenbuch, Bruno (advisor), Klaassen, Curtis D. (cmtemember), Reed, Gregory A. (cmtemember), Guo, Grace (cmtemember), Blanco, Gustavo (cmtemember).

Subjects/Keywords: Health sciences; Pharmacology; Biology; Physiology; Oatp; Organic anion; Perfluoronated carboxylates; Pfca; Structure; Transporters

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Weaver, Y. M. (2010). STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/7394

Chicago Manual of Style (16^th Edition):

Weaver, Yi Miao. “STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT.” 2010. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/7394.

MLA Handbook (7^th Edition):

Weaver, Yi Miao. “STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT.” 2010. Web. 28 Jan 2021.

Vancouver:

Weaver YM. STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT. [Internet] [Doctoral dissertation]. University of Kansas; 2010. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/7394.

Council of Science Editors:

Weaver YM. STRUCTURAL REQUIREMENTS OF ORGANIC ANION TRANSPORTING POLYPEPTIDE MEDIATED TRANSPORT. [Doctoral Dissertation]. University of Kansas; 2010. Available from: http://hdl.handle.net/1808/7394

University of Kansas

13. Shawgo, Mary E. NEW INSIGHTS INTO THE REGULATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION DURING APOPTOSIS.

Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2009, University of Kansas

URL: http://hdl.handle.net/1808/5943

► Disruption of normal apoptosis can contribute to the onset of cancer. Additionally, many cancer drugs are effective for their ability to initiate the apoptotic process.… (more)

▼ Disruption of normal apoptosis can contribute to the onset of cancer. Additionally, many cancer drugs are effective for their ability to initiate the apoptotic process. Often this involves the activation of the mitochondria-mediated pathway. The existing paradigm of mitochondria-mediated apoptosis, which can be activated by DNA damage, indicates this pathway proceeds in a linear fashion. Mitochondria outer membrane permeabilization (MOMP) and the release of intermembrane space proteins (e.g., cytochrome c) are early events during mitochondria-mediated apoptotic signaling. In addition, Apaf-1 is a critical component of the mitochondrial pathway and is generally thought to reside downstream of MOMP. My dissertation investigates the molecular requirements essential for MOMP during stress-induced and receptor-mediated apoptosis. Distinct clones of Jurkat T-lymphocytes were used in which the mitochondria-mediated pathway had been inhibited at three different steps. The first aim investigated the molecular requirements necessary for Bak activation. Apaf-1-deficient cells and cells overexpressing full-length XIAP or the BIR1/BIR2 domains of XIAP were refractory mitochondrial apoptotic events. These data suggest that caspase-mediated positive amplification of initial mitochondrial changes can determine the threshold for irreversible activation of the intrinsic apoptotic pathway. In so-called types II cells, the mitochondria-mediated pathway is required for cell death upon stimulation of the receptor-mediated pathway. In the second aim, I investigated the molecular requirements necessary for Fas-mediated apoptosis. Interestingly, Apaf-1-deficient type II Jurkat cells were sensitive to anti-Fas. Inhibiting downstream caspases decreased all anti-Fas-induced apoptotic changes. Combined, my findings strongly suggest that Fas-mediated activation of executioner caspases and induction of apoptosis does not depend on apoptosome-mediated caspase-9 activation in prototypical type II cells. In the third aim, mitochondrial apoptotic events were examined after prolonged treatment with etoposide ( 6 h). Total cellular cytochrome c and Smac were decreased after 24 h of incubation. Interestingly, inhibition of the 26S proteasome by co-treatment of Apaf-1-deficient cells with bortezomib or MG132 led to the robust retention of total cellular cytochrome c and Smac. Combined, the major findings suggest that proteasomal degradation is largely responsible for the loss of intracellular cytochrome c and Smac in Apaf-1-deficient cells incubated with etoposide over extended time periods. Advisors/Committee Members: Robertson, John D (advisor), Durham, Dianne (cmtemember), Imig, Thomas J. (cmtemember), Jaeschke, Hartmut (cmtemember), Reed, Gregory A. (cmtemember), Zhu, Bao-Ting (cmtemember).

Subjects/Keywords: Health sciences; Pharmacology; Cell biology; Apoptosis; Cancer; Chemotherapy

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APA (6^th Edition):

Shawgo, M. E. (2009). NEW INSIGHTS INTO THE REGULATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION DURING APOPTOSIS. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/5943

Chicago Manual of Style (16^th Edition):

Shawgo, Mary E. “NEW INSIGHTS INTO THE REGULATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION DURING APOPTOSIS.” 2009. Doctoral Dissertation, University of Kansas. Accessed January 28, 2021. http://hdl.handle.net/1808/5943.

MLA Handbook (7^th Edition):

Shawgo, Mary E. “NEW INSIGHTS INTO THE REGULATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION DURING APOPTOSIS.” 2009. Web. 28 Jan 2021.

Vancouver:

Shawgo ME. NEW INSIGHTS INTO THE REGULATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION DURING APOPTOSIS. [Internet] [Doctoral dissertation]. University of Kansas; 2009. [cited 2021 Jan 28]. Available from: http://hdl.handle.net/1808/5943.

Council of Science Editors:

Shawgo ME. NEW INSIGHTS INTO THE REGULATION OF MITOCHONDRIAL OUTER MEMBRANE PERMEABILIZATION DURING APOPTOSIS. [Doctoral Dissertation]. University of Kansas; 2009. Available from: http://hdl.handle.net/1808/5943

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